Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing
Open accessAbstract
Innate immune sensing of dying cells is modulated by several signals. Inflammatory chemokines-guided early recruitment, and pathogen-associated molecular patterns-triggered activation, of major anti-pathogenic innate immune cells like neutrophils distinguishes pathogen-infected stressed/dying cells from sterile dying cells. However, whether certain sterile dying cells stimulate innate immunity by partially mimicking pathogen response-like recruitment/activation of neutrophils remains poorly understood. We reveal that sterile immunogenic dying cancer cells trigger (a cell autonomous) pathogen response-like chemokine (PARC) signature, hallmarked by co-release of CXCL1, CCL2 and CXCL10 (similar to cells infected with bacteria or viruses). This PARC signature recruits preferentially neutrophils as first innate immune responders in vivo (in a cross-species, evolutionarily conserved manner; in mice and zebrafish). Furthermore, key danger signals emanating from these dying cells, that is, surface calreticulin, ATP and nucleic acids stimulate phagocytosis, purinergic receptors and toll-like receptors (TLR) i.e. TLR7/8/9-MyD88 signaling on neutrophil level, respectively. Engagement of purinergic receptors and TLR7/8/9-MyD88 signaling evokes neutrophil activation, which culminates into H 2 O 2 and NO-driven respiratory burst-mediated killing of viable residual cancer cells. Thus sterile immunogenic dying cells perform 'altered-self mimicry' in certain contexts to exploit neutrophils for phagocytic targeting of dead/dying cancer cells and cytotoxic targeting of residual cancer cells.
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Enzymatic degradation of extracellular nucleic acids limits immunogenicity of RCD.
“In line with this notion, the enzymatic degradation of extracellular nucleic acids considerably limits the immunogenicity of RCD [864, 875].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [864]
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- Authors
- Garg, A. D., Vandenberk, L., Fang, S., Fasche, T., Van Eygen, S., Maes, J., Van Woensel, M., Koks, C., Vanthillo, N., Graf, N., de Witte, P., Van Gool, S., Salven, P., & Agostinis, P.
- Affiliations
- University of Helsinki (FI)
- KU Leuven (BE)
- Saarland University (DE)
- Corresponding author
- Garg, Abhishek D
- Agostinis, Patrizia
- Venue
- Cell Death & Differentiation
- Published
- 2017-02-24
- Volume
- 24
- Issue
- 5
- Pages
- 832-843
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5423108
- OpenAlex
- W2589742139
- Cited by
- 120
- References
- 35
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 11 · 2023: 14 · 2022: 13 · 2021: 19 · 2020: 20 · 2019: 14 · 2018: 11 · 2017: 9
- FWCI
- 6.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Olivia Fund
- Fonds Wetenschappelijk Onderzoek (K202313N, GA01111N, G058412N)
- KU Leuven
- Vlaamse regering
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- neutrophil recruitment, neutrophil activation, cancer cell death, CXCL1, MCP-1, CXCL10, calreticulin, ATP, purinergic receptors, Toll-like receptors, neutrophil respiratory burst, hydrogen peroxide, nitric oxide, phagocytosis, innate immunity
- MeSH terms
- Animals, Cytotoxicity, Immunologic, Epithelial Cells, Female, Gene Expression Regulation, Humans, Male, Melanocytes, Mice, Inbred C57BL, Neuroglia, Neutrophils, Zebrafish, Signal Transduction, Apoptosis, Coculture Techniques, Chemokine CCL2, Chemokines, CC, Animals, Genetically Modified, Cell Line, Tumor, Toll-Like Receptor 7, Mice, Myeloid Differentiation Factor 88, Chemokine CXCL10, Chemokine CXCL1
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